Lack of association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults.

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.

Do children with lupus have fewer male siblings?

It is widely acknowledged that genetic factors play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). However, the female preponderance remains unexplained. We hypothesized that the female preponderance in childhood SLE results from selection early in the course of conception against male fetuses bearing genetic material predisposing to SLE. If this hypothesis is accurate, there should be a decreased number of male children in families with a child with SLE. Alternatively, children with SLE would have fewer male siblings. Further, this hypothesis may apply to other diseases with a female predominance such as pauciarticular onset juvenile rheumatoid arthritis (PaJRA), and not apply to diseases without female preponderance such as systemic onset juvenile rheumatoid arthritis (SoJRA). Chart review of patients with childhood onset SLE and PaJRA revealed a greater number of female children in these families compared with families of patients with SoJRA. Large-scale epidemiologic studies with precise counting of miscarriages and abortions could help to confirm these findings. Detailed studies of genetic and maternal intrauterine factors are required to conclusively prove this hypothesis.

Quality of life in children with systemic lupus erythematosus: a review.

Systemic lupus erythematosus (SLE) in children is a chronic multisystem disease with wide ranging effects on their quality of life (QOL). While SLE's impact on different arenas of life and well-being has been extensively examined in the adult population, its effect on children has not received adequate attention. This review discusses the multidimensional aspect of QOL, the biopsychosocial implications of SLE, factors complicating QOL measurement in the affected population, and the different generic and disease-specific scales used for measuring QOL and related constructs. Until now, there have not been any pediatric SLE-specific health-related QOL (HRQOL) scales. A section is devoted to a novel instrument developed specifically for measuring QOL in pediatric lupus called the Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY). SMILEY is a brief, easily understood, valid, reliable and internally consistent pediatric SLE-specific QOL scale and will be a useful adjunct to clinical trials and outcomes research.

Relationship of quality of life and physical function measures with disease activity in children with systemic lupus erythematosus.

The objective of this study is to assess relationship of systemic lupus erythematosus (SLE) activity with quality of life (QOL) and physical function and determine which is more closely correlated with SLE activity in children; and identify factors critical to children's QOL. In this cross-sectional study, children with SLE and parents completed corresponding versions of physical function (Childhood Health Assessment Questionnaire CHAQ), and QOL (Pediatric Quality of Life Inventory-PedsQL Generic/Rheumatology modules) questionnaires. SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), severity, self-concept and socioeconomic status (SES) were measured. For 24 children, CHAQ scores significantly correlated with SLEDAI (rho = 0.4, p = 0.04), SDI (rho = 0.6, p = 0.004), and associated with severity (p = 0.03). PedsQL scores did not significantly correlate with above parameters. Higher self-concept/SES correlated (p < 0.05) with better physical function and QOL. For 19 parents, the only significant correlation was between SLEDAI and Worry domain-Rheumatology module (rho = 0.5, p = 0.01). Lack of strong correlation of disease activity with QOL and physical function suggests that they are different constructs with partial overlap, and should be considered collectively while evaluating the impact of SLE on children/families. Self-concept and SES should be assessed while measuring QOL in children. Larger sample is required to confirm results.

Quality of life in paediatric lupus.

Paediatric systemic lupus erythematosus (SLE) is associated with significant morbidity and has biopsychosocial implications resulting from the disease and its treatment. The aim of this study was to identify domains of quality of life (QOL) impacted by SLE in children. Children with SLE and their parents were asked a single open-ended question related to lupus. Themes derived from children's responses focused primarily on coping and maintaining control of their life despite SLE. Themes from the parents' responses were twofold: a) efforts to cope with their child having SLE; and b) appreciation/sadness in connection with their children's coping process. Qualitative exploration of different facets of QOL in these children is critical for the understanding of specific factors that assist/ease the coping process and formulating interventions for improving children's/family's self-efficacy and disease management.

Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis.

OBJECTIVE: To evaluate the efficacy and safety of combining monthly intravenous methotrexate (IV MTX) with monthly IV cyclophosphamide (CYTX; given on the same day) for the treatment of children who develop recurrent diffuse proliferative glomerulonephritis secondary to systemic lupus erythematosus during or after the standard 3 year course of IV CYTX. METHODS: Five children were treated with nine monthly doses of IV CYTX (750-1000 mg/m(2)/month) and IV MTX (50-300 mg/m(2)/month) given on the same day. Their clinical and laboratory measurements were collected every other week throughout the nine months. RESULTS: All children improved dramatically. SLEDAI scores decreased from an average of 13.8 to 4.4, mean (SD) serum creatinine level fell from 100 (60) to 80 (40) micro mol/l, and serum albumin rose from 28 (11) g/l to 41 (6) g/l, while the mean (SD) C3 level increased from 0.5 (0.1) g/l to 0.9 (0.4) g/l. Clinical improvement persisted after 4 years' follow up despite discontinuing MTX and CYTX after 9 months. The average daily dose of corticosteroids has been reduced from 27.6 mg/day at the start of treatment to 12.5 mg/day at follow up. CONCLUSION: Combined IV MTX and IV CYTX treatment effectively controls recurrent or refractory lupus nephritis in children with significant disease activity after treatment with IV CYTX alone.

Advances in the medical treatment of juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis (JRA) remains a challenge for clinicians. Nonsteroidal anti-inflammatory drugs and corticosteroids remain the mainstays of therapy, but concerns persist about side effects and the ability of these agents to prevent progression of bony disease. In recent years, novel treatments have been developed and quickly discarded because of unexpected toxicities or lack of efficacy. However, recent studies have shown that methotrexate and sulfasalazine are relatively safe and effective for JRA. Newly developed drugs, such as selective cyclooxygenase-2 inhibitors and soluble tumor necrosis factor receptor, whose development has stemmed from a more basic understanding of pathophysiology, may provide better disease control with fewer side effects. Finally, novel therapies, such as stem cell transplantation, may offer hope for children with JRA, especially systemic-onset JRA, whose disease has been refractory to conventional therapy.

Levels of soluble Fas/APO-1/CD95 in systemic lupus erythematosus and juvenile rheumatoid arthritis.

OBJECTIVE: To quantify soluble Fas/APO-1 (sFas/APO-1) protein in the serum of patients with systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA). METHODS: Soluble Fas/APO-1 was quantified using a sandwich enzyme-linked immunosorbent assay. Disease activity in SLE patients was assessed by the SLE Disease Activity Index. RESULTS: Increased serum sFas/APO-1 levels were observed in only 1 of the 27 SLE patients (4%) and 3 of the 10 JRA patients (30%). CONCLUSION: Increased levels of sFas/APO-1 occurred infrequently in SLE, and the levels were lower than 10 ng/ml. Increased levels of sFas/APO-1 are not specific for SLE. Soluble Fas/APO-1 is unlikely to be of major pathogenetic significance in SLE.

Expression and function of the murine CD95/FasR/APO-1 receptor in relation to B cell ontogeny.

Mice defective in Fas-mediated apoptosis (lpr phenotype) have an intrinsic B cell abnormality that predisposes them to autoantibody production. To investigate potential roles for the Fas receptor (FasR) in B cell tolerance, FasR expression and function were evaluated at different stages of B cell development. FasR expression was very low or absent on pro- and pre-B cells, but was detected in early B cell lines and was up-regulated following IFN-gamma-induced maturation of the pre-B cell line 70-Z. Whereas FasR expression was very low in resting mature sIgM+ B cells, expression was markedly increased following mitogen activation and was also elevated in two mature sIgG+ lymphoma lines. FasR expression correlated strongly with the ability of B cells to undergo Fas-mediated apoptosis. In addition, although Fas did not appear to play a direct role in apoptosis mediated by cross-linking of sIg with anti-IgM, anti-FasR and sublethal concentrations of anti-Ig were additive in the induction of apoptosis in the early B cell line WEHI 231. These findings suggest that the Fas pathway is not involved in the elimination of pro- and pre-B cells, but are compatible with an ancillary role for FasR in the elimination of early B cells and elimination of mature B cells following activation.